Characterization of the neuronal circuits mediating drug reinforcement would be beneficial in understanding the neurobiological basis of abuse disorders. The major goal of this research project is to identify and characterize the brain loci, neurohumor receptors and neuronal circuits that initiate and mediate the reinforcing effects of cocaine. Brain sites where cocaine initiates this activity are under investigation with intracranial self-administration methodologies. The medial prefrontal cortex is one such site while the ventral tegmental area and nucleus accumbens do not support self-administration. During this next grant period the amygdala, sulcal-rhinal cortex, lateral hypothalamus, olfactory tubercle and caudate nucleus-putamen will be assessed for self-administration. Two lever discrimination procedures and intermittent schedules of reinforcement will be used to evaluate the reinforcing effects of the drug whereas pharmacological blockade and neurotoxin lesions of the self- administration site will result in the characterization of the neurotransmitter receptors and neurons responsible for these effects. The ability of amphetamine to initiate reinforcing neuronal activity at these and other brain sites will also be evaluated. Neuronal circuits mediating the reinforcing properties of cocaine will continue to be characterized by measuring the turnover rates of biogenic amine and amino acid neurotransmitters in small brain regions of rats intravenously self-administering the drug and comparing these with littermates receiving either identical yoked infusions of cocaine or the vehicle. Turnover rates of these neurotransmitters will also be determined in discrete brain regions of rats intracranially self-administering cocaine into the medial prefrontal cortex or receiving yoked vehicle injections. Behavioral specificity will be assessed by lesioning the neurons identified to be involved with selective neurotoxins in rats lever pressing on concurrent schedules of food, water and intravenous cocaine presentation. These combined methodologies should continue to characterize the biological mechanisms of the reinforcing effects of cocaine. Such information could be beneficial for the development of therapeutic approaches for the treatment of compulsive cocaine use.